Project Summary/Abstract Brain-derived neurotrophic factor (BDNF) is implicated in numerous cellular actions that are both adaptive and maladaptive in nature. For nearly two decades, it has been proposed that BDNF signaling through its high affinity receptor TrkB, plays a role in inflammatory and nerve injury- induced neuropathic pain. However, whether BDNF-TrkB signaling is also critically involved in the development or maintenance of chronic neuropathic pain after spinal cord injury (SCI) remains unsolved. We hypothesize that cutaneous BDNF promotes primary afferent hyperexcitability and thus pain after SCI, thereby arguing that peripheral, but not central, BDNF signaling is more critical to the expression of SCI-induced pain. In SA1, behavioral studies will compare the effect of peripheral BDNF signaling on formalin- induced inflammatory pain, and neuropathic pain after peripheral nerve and spinal cord injury. Experiments will be undertaken in mice with a mutated TrkB receptor (TrkBF616A mice) that allows selective and reversible blockade of BDNF signaling, and mice in which BDNF is selectively knocked out in primary afferents (BDNF-cKO mice) - derived from crossing BDNFFl/Fl mice with Advillin-Cre mice. In SA2, an ex-vivo skin-nerve electrophysiology preparation will be used to examine the effect of increased BDNF in the skin on neural activity evoked by stimulation of primary afferents innervating the trunk skin, in these transgenic strains. We will also undertake cellular assessment to examine changes in the expression of BDNF, TrkB and several key downstream signaling proteins in the skin after inflammatory and neuropathic pain. This novel exploratory study will be the first to identify the important and specific role peripheral BDNF signaling, including cutaneous derived BDNF, plays in primary afferent hyperexcitability and pain, including neuropathic pain after SCI. The results obtained here will provide new insight into the peripheral neurophysiological mechanisms that underlie maladaptive sensory processing and pain after SCI.